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J. Biol. Chem., Vol. 277, Issue 26, 23172-23180, June 28, 2002
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From the Neuroblastoma (NB), a malignant
childhood tumor deriving from the embryonic neural crest, is sensitive
to the growth-stimulating effects of insulin-like growth factors
(IGFs). Aggressive cases of this disease often acquire autocrine loops
of IGF production, but the mechanisms through which the different
components of the IGF axis are regulated in tumor cells remain unclear.
Upon conditional expression of c-Myb in a NB cell line, we
detected up-regulation of IGF1, IGF1 receptor, and insulin-like
growth factor-binding protein 5 (IGFBP-5) expression. Analysis of
the IGFBP-5 promoter revealed two potential Myb binding
sites at position
Expression of Insulin-like Growth Factor-binding Protein 5 in Neuroblastoma Cells Is Regulated at the Transcriptional Level by
c-Myb and B-Myb via Direct and Indirect Mechanisms*
§,,,,,,
Ente Nuove Tecnologie Energia Ambiente
(ENEA), Section of Toxicology and Biomedical Sciences, Via
Anguillarese 301, 00060 S. Maria di Galeria, Rome, Italy and
¶ Kimmel Cancer Center, Thomas Jefferson University,
Philadelphia, Pennsylvania 19107
59 to 54 (M1) and 429 to 424 (M2) from the
transcription start site; both sites were bound by c-Myb and B-Myb
in vitro and in vivo. Reporter assays carried
out using the proximal region of the human IGFBP-5 promoter
demonstrated that c-Myb and B-Myb enhanced transcription. However,
site-directed mutagenesis and deletion of the Myb binding sites coupled
with reporter assays revealed that M2 but not M1 was important for
Myb-dependent transactivation of the IGFBP-5 promoter. The double mutant M1/M2 was still transactivated by c-Myb,
suggesting the existence of Myb binding-independent mechanisms of
IGFBP-5 promoter regulation. A constitutively active AKT
transactivated the IGFBP-5 promoter, whereas the
phosphatidylinositol 3-kinase inhibitor LY294002 suppressed it.
Moreover, the kinase dead dominant negative K179M AKT mutant was able
to inhibit transcription from the M2 and M1/M2
IGFBP-5 mutant promoters. Deletion analysis of the
IGFBP-5 promoter revealed that the AKT-responsive
region lies between nucleotides 334 and 83. Together, these data
suggest that the Myb binding-independent transactivation of the
IGFBP-5 promoter was due to the activation of the
phosphatidylinositol 3-kinase/AKT pathway likely mediated by IGF1
receptor-dependent signals. Finally, IGFBP-5 was able to
modulate proliferation of NB cells in a manner dependent on its
concentration and on the presence of IGFs.
*
This work was supported in part by the Associazione Italiana
per la Ricerca sul Cancro, the Associazione per la lotta al
Neuroblastoma (G. R.), and the National Cancer Institute (B. C.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed. Tel.:
39-063048-3172; Fax: 39-063048-6559; E-mail:
raschella@casaccia.enea.it.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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